DESC:“NOVEL CRYSTALLINE FORM OF SELEXIPAG AND PROCESS FOR THE PREPARATION THEREOF”

TECHNICAL FIELD
The present invention provides a novel crystalline form of Selexipag compound of formula (I) and process for the preparation thereof.

BACKGROUND OF THE INVENTION
Selexipag (2-{4-[(5, 6-diphenylpyrazin-2-yl) (isopropyl) amino] butoxy}-N-(methylsulfonyl) acetamide) is a prostacyclin receptor (PGI2) agonist, which leads to vasodilation in the pulmonary circulation. It is indicated for the treatment of pulmonary arterial hypertension (PAH). Selexipag was approved in USA on December 21, 2015 as tablet; oral-0.2mg, 0.4mg, 0.6mg, 0.8mg, 1mg, 1.2mg, 1.4mg and 1.6mg and it is marketed by Actelion Pharmaceuticals Ltd under tread name Uptravi®. The Selexipag is structurally represented a formula-I.

Formula-I
Selexipag and a process for its preparation is disclosed in U.S. patent 7,205,302.
U.S. patent 8,791,122 discloses crystalline form of Selexipag, designated as form I having an X-ray powder diffraction pattern with specific peaks at 9.4, 9.8, 17.2 and 19.4 degrees 2-theta., form II having an X-ray powder diffraction pattern with specific peaks at 9.0, 12.9, 20.7 and 22.6 degrees 2-theta, form III having an X-ray powder diffraction pattern with specific peaks at 9.3, 9.7, 16.8, 20.6 and 23.5 degrees 2-theta.

The US'122 also discloses an amorphous form of Selexipag, and a process for preparing it. As per the process exemplified in the US'122, the amorphous form of Selexipag is prepared by dissolving Selexipag in a 1,3,5-trimethylbenzene, followed by heating and cooling treatment to the solution to obtain amorphous powder by filtration.

WO2017040872A1 discloses crystalline form of Selexipag, designated as form IV having an X-ray powder diffraction pattern with specific peaks at 4.3, 6.5, 11.9, 16.2, 18.0, 19.1 and 21.0 ± 0.2 degrees 2-theta and form V having an X-ray powder diffraction pattern with specific peaks at 3.8, 11.5, 13.0, 17.9, 20.7, and 21.1 ± 0.2 degrees 2-theta.

Selexipag is known to provide a variety of polymorphs having distinct crystal structures and physical properties like melting point, DSC, X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint etc. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

It has been disclosed earlier that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline forms. For some therapeutic indications one bioavailability pattern may be favored over another.

Discovering new solid state forms of a pharmaceutical product like Selexipag can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, improved dissolution profile, or improved shelf-life. There remains a need to provide stable, commercially viable and advantageous solid state forms of Selexipag.

OBJECT OF THE INVENTION
One object of the present invention is providing a novel crystalline polymorphic form of Selexipag compound of Formula-I which is characterized by X-ray diffraction pattern peaks at 8.6, 15.8, 16.0, 23.4, 24.0 and 29.4 ± 0.2 degrees two theta.

Yet another object of the present invention is to provide a process for the preparation of crystalline form of Selexipag compound of Formula-I.

Yet another object of the present invention is to provide a process for the preparation of amorphous form of Selexipag compound of Formula-I.

SUMMARY OF THE INVENTION
The present inventors have now surprisingly and unexpectedly found a novel crystalline form of Selexipag. The novel crystalline form of Selexipag is consistently reproducible and is found to be stable. The novel crystalline form disclosed herein exhibits properties making it suitable for pharmaceutically acceptable salt.

In the first embodiment, the present application provides novel crystalline form of Selexipag compound of Formula-I which is characterized by X-ray diffraction pattern peaks at 8.6, 15.8, 16.0, 23.4, 24.0 and 29.4 ± 0.2 degrees two theta as depicted in figure 1.

In another embodiment, the present application provides a process for preparing novel crystalline form of Selexipag comprises;
a. dissolving Selexipag in solvent system at a temperature ranging from 50? to reflux temperature;
b. cool the solution at a temperature between 10-20?C;
c. isolating the product by filtration.

In another embodiment, the present application provides a process for preparing amorphous form of Selexipag comprises;
a. dissolving Selexipag in solvent system at room temperature;
b. obtaining amorphous form of Selexipag by the removal of the solvent.

BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is an illustration of powder X-ray diffraction (PXRD) of a new crystalline form of Selexipag compound of formula-I prepared according to Example 1.

Figure 2 is illustrates Differential scanning calorimetric (DSC) thermogram of novel crystalline form of Selexipag compound of formula-I prepared according to Example 1.

Figure 3 is illustrates infra red (IR) spectrum of novel crystalline form of Selexipag compound of formula-I prepared according to Example 1.

Figure 4 is illustrates Differential scanning calorimetric (DSC) thermogram of a solid dispersion comprising Selexipag form-I, form-II and form-III (1:1:1 w/w/w) prepared.

Figure 5 is illustrates Differential scanning calorimetric (DSC) thermogram novel crystalline form, form-I, form-II and form-III (1:1:1:1 w/w/w/w) of Selexipag.

Figure 6 is an illustration of powder X-ray diffraction (PXRD) of an amorphous form of Selexipag compound of formula-I prepared according to Example 2.

Figure 7 is illustrates Differential scanning calorimetric (DSC) thermogram of an amorphous form of Selexipag compound of formula-I prepared according to Example 2.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention is to provide a novel crystalline form of Selexipag compound of formula-I has an X-ray diffraction pattern with peaks at 8.2, 8.8, 16.8, 19.7, 22.0, 22.5, and 24.8 ± 0.2 degrees two theta.

Novel crystalline form of Selexipag compound of formula-I further characterized by X-ray diffraction intensity with the diffraction angle 2? as shown in Table 1 and an X-ray diffraction pattern as shown in FIG. 1.

Novel crystalline form of Selexipag compound of formula-I further characterized by DSC thermograph which shows endotherm with onset temperature of approximately 127?C and a malting peak approximately 128.6?C as shown in FIG.2.

Novel crystalline form of Selexipag compound of formula-I further characterized by IR spectrum as shown in FIG. 3.

The present invention is to provide a process for the preparation of novel crystalline form of Selexipag comprising steps of:
a. dissolving Selexipag in solvent system at a temperature ranging from 50? to reflux temperature;
b. cool the solution at a temperature between 10-20?C;
c. isolating the product by filtration.

Examples solvent system selected from the group consisting of (C1-C4) alcohol include methanol, ethanol, propanol, isopropanol, tert-butanol, methyl isopropyl ketone (MIPK), ethyl acetate, 1,4-Dioxane, acetone, acetonitrile and mixture(s) thereof. Preferably tert-butanol.

In a typical crystallization process, the Selexipag is dissolved in one or more solvents as provided above. To obtain solution, the solvent may have to be heated. Heating is preferably carried out to a temperature ranging from 50?to reflux temperature, more preferably 80?-85?C for the time period of 30-90 minutes to obtained clear solution. The hot clear solution then preferably allowed to cool, such to a temperature range from 5?-20?C, more preferably 15?C and stirred for about 20-60 minutes. Resulting the precipitation of crystalline Selexipag, filter and dry the obtained solid to get crystalline form of Selexipag characterized by an X- ray powder 8.2, 8.8, 16.8, 19.7, 22.0, 22.5, and 24.8 ± 0.2 degrees two theta. The obtained product having HPLC purity NLT 99.0 % with no individual impurity greater than 0.15%.

Crystallization include adding an anti-solvent to facilitate the precipitation of compound. The term “anti-solvent” refers to liquid that, when added to a solution of compound in a solvent, includes precipitation of compound. The anti-solvent may also be in a binary mixture with the solvent when the solution prepared. Suitable anti-solvent include water and C5-C12 cyclic or acyclic saturated hydrocarbons. Preferred anti-solvents include water, heptane, and hexane.

The resulting crystals are then recovered by conventional technique, such as filtration. The crystals are preferably dried. The temperature may be increased or the pressure reduced to accelerate the drying process. Drying may be carried out a temperature of about 40? to about 100?C, under a pressure of below about 100mmHg. Preferably, drying occurs at a temperature of about 60?C.

Table 1: Novel crystalline form of Selexipag compound of formula-I has an X-ray diffraction pattern with peaks at approximately;
2 Theta d value Intensity % 2 Theta d value Intensity %
4.4905 19.6618 3.15 21.5789 4.1148 31.00
8.2217 10.7454 18.82 22.0291 4.0317 100.0
8.8989 9.9291 76.39 22.5377 3.9419 82.21
12.8489 6.8842 22.02 23.7923 3.7368 12.29
13.4835 6.5616 9.20 24.8198 3.5843 26.65
14.9712 5.9127 5.35 25.4376 3.4987 19.99
16.1211 5.4935 15.01 26.9386 3.3070 11.84
16.8190 5.2671 88.09 28.9218 3.0846 19.93
17.1632 5.1622 26.66 29.6340 3.0121 14.03
17.5684 5.0440 19.91 30.8232 2.8985 7.61
18.4643 4.8013 9.06 33.5188 2.6713 7.65
18.9320 4.6837 14.32 34.4182 2.6036 9.91
19.7300 4.4960 26.79 37.6253 2.3887 4.60
20.6693 4.2938 13.30 - - -

Comparison of major XRPD values, DSC and melting point/range of existing crystalline Form-I, II and III of Selexipag reported in U.S. patent 8,791,122 with novel crystalline form of Selexipag of the present invention is shown in table-2.

Table 2:
Selexipag Form-I Form-II Form-III New crystalline form
Melting Point/range reported 140.4 135.2 138.0 -
Melting Point/range observed 137-139 132-135 136-138 126-130
DSC
observed Peak = 140.1
Onset = 137.0 Peak = 135.9
Onset = 133.3 Peak = 136.7
Onset = 134.5 Peak = 128.6
Onset = 127.0
Major 2 theta (?) values 9.4 9.0 9.3 8.2
9.8 12.9 9.7 8.8
17.2 20.7 16.8 16.8
19.4 22.6 20.6 22.0
- - 23.5 22.5
- - - 24.8

The present invention also provides a novel process for the preparation of amorphous Selexipag comprising steps of:
a. dissolving Selexipag in solvent system at room temperature;
b. obtaining amorphous form of Selexipag by the removal of the solvent.

As used herein, the terms "obtaining" means isolating the amorphous form of Selexipag by way of filtration, filtration under vacuum, centrifugation, decantation. The product obtained may be further or additionally dried to achieve the desired moisture values.

In general, solvent system use in step a) for the preparation of amorphous form of Selexipag comprise one or more chlorinated solvents, alcoholic solvents, Ketone solvents. In particular methylene dichloride, ethylene dichloride, chlorobenzene, methanol and mixture(s) thereof.

Step b) involves removal of the solvent to obtain an amorphous form of Selexipag. The isolation may be affected by removing solvent. Techniques which may be used for the removal of solvent include distillation, distillation under vacuum, spray drying, agitated thin film drying ("ATFD"), and freeze drying (lyophilization).

Selexipag is dissolved in one or more chlorinated or alcoholic solvent as provided above at room temperature for 1-3 hours. Clear filtration followed by complete removal of solvent to obtain a amorphous form of Selexipag which has an X-ray diffraction pattern as shown in Fig. 6 and DSC pattern as shown in Fig.7.

When used in reference to a peak in an X-ray powder diffraction pattern (PXRD), the term "approximately" means that the peak may vary by ±0.2 degrees 2-theta of the subject value. When used in reference to a peak in a DSC thermogram, the term "approximately" means that the peak may vary by ±1 °C of the subject value.

X-Ray Powder Diffraction Method: Explain--The X-ray powder diffraction pattern was measured with X’Pert PRO X-ray powder diffractometer, equipped with copper IR radiation source = 1.54184 A°, X’celerator (2.022° 2?) detector.
Scanning parameter- Angle range-3-40 deg. Step size- 0.0167, time per step- 50.165 sec, continuous scan.

DSC Method: Explain DSC analysis was performed on Perkin-Elmer Pyris bU with heating rate of 10 °C/min, under nitrogen flow of 30 ml/min. A hermetic aluminium closed pan without hole was used and sample mass was about 2-5 mg.

Melting Point method:
Instrument: DBK PROG (Serial No. 120970)
Method: Heating rate was adjusted to 1.0°C/min

IR Method:
Instrument: Perkin Elmer Spectrum one (Serial No. 53302)
Method: KBr pallet of sample scanned in range 400 to 4000 cm-1
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims

EXAMPLES
Example 1: Preparation of novel crystalline polymorph of Selexipag of formula I
Selexipag (100 gm) and tert-Butanol (1800 ml) was taken in an assembly and heated the reaction mass to 85°C for 1-2 h. Mixture was filtered through celite bed at 75°C to obtain clear solution. Resulted solution was cooled to 15°C in 30-45 mins. The resulting precipitate was filtered and dried to obtain new polymorph of Selexipag of Formula-I.

EXAMPLE-2: Preparation of amorphous form of Selexipag of Formula-I:
Selexipag (100 gm) dissolved in dichloromethane (500 ml) and reaction mass was stirred at room temperature for 1 h. Mixture was filtered through celite bed at to obtain clear solution. Dichloromethane was distilled out completely. The resulting compound was collected to obtain amorphous form of Selexipag of Formula-I.

Example 3: Preparation of novel crystalline polymorph of Selexipag of formula I
Selexipag (1.00 gm) and methyl isopropyl ketone (15.00 ml) was taken in an assembly and heated the reaction mass to 65-75°C for 1-2 h. Mixture was filtered through celite bed at 60-75°C to obtain clear solution. Addition of hexane (10.00 ml) in reaction mixture and resulted solution was cooled to -10°C in 4-10 hrs. The resulting precipitate was filtered and dried to obtain new polymorph of Selexipag of Formula-I.

Example 4: Preparation of novel crystalline polymorph of Selexipag of formula I
Selexipag (1.0 gm) and 1,4-Dioxane (7.0 ml) was taken in an assembly and heated the reaction mass to 45-50°C. Mixture was filtered through celite bed at 75°C to obtain clear solution. Resulted solution was cooled to 25-30°C in 30-45 mins. Addition of water (6.0 ml) in reaction mixture and resulted solution was stirred for 2-4 hrs The resulting precipitate was filtered and dried to obtain new polymorph of Selexipag of Formula-I.

Although the invention has been described with reference to specific embodiments, it is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments and alternate embodiments of the said invention will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the true spirit or scope of the present invention as exemplified and claimed herein below.
,CLAIMS:We Claim:
1. A crystalline form of Selexipag compound of Formula-I which is characterized by X-ray diffraction pattern peaks at 8.2, 8.8, 16.8, 19.7, 22.0, 22.5, and 24.8 ± 0.2 degrees two theta.

2. The crystalline form of Selexipag compound of Formula-I of claim 1, wherein crystalline form of Selexipag compound of Formula-I has a DSC thermograph with endotherm onset temperature of approximately 127?C and malting peak approximately 128.6?C.

3. A process for preparation of crystalline form of Selexipag comprising steps of ;
a. dissolving Selexipag in solvent system at a temperature ranging from 50?C to reflux temperature;
b. cool the solution at a temperature between 10-20?C;
c. isolating the product by filtration.

4. The process as claimed in claim 3, wherein the solvent system is selected from (C1-C4) alcohol include methanol, ethanol, propanol, isopropanol, tert-butanol, methyl isopropyl ketone (MIPK), ethyl acetate, 1,4-Dioxane, acetone, acetonitrile and mixture(s) thereof.

5. The process as claimed in claim 3, wherein the solvent is tert-butanol.

6. A process for preparation of amorphous Selexipag comprising steps of:
a. dissolving Selexipag in solvent system at room temperature;
b. obtaining amorphous form of Selexipag by the removal of the solvent.

7. The process as claimed in claim 6, wherein the solvent system is selected from one or more chlorinated solvents, alcoholic solvents and Ketone solvents.

8. The process as claimed in claim 6, wherein the solvent is selected from methylene dichloride, ethylene dichloride, chlorobenzene, methanol and mixture(s) thereof.

9. The process as claimed in claim 6, wherein the solvent is methylene dichloride.

10. The process as claimed in claim 6, wherein amorphous Selexipag is characterized by Fig. 6.

Dated this 13th Day of February 2019
For UNICHEM LABORATORIES LTD.,

Gautam Bakshi
Head – IPM
IN/PA 1069